tbuckley/cabot-search huggingface dataset:
“[He] can be supportive, but at times I feel he is ashamed of me”: Understanding the relationship between parental support and quality of life amongst trans and gender diverse youth in the UK
Authors: Abby Barras, Bethany A. Jones
Journal: International Journal of Transgender Health (2023)

Background Trans and gender diverse (TGD) youth often report poor relations with their parents and perceive these to be core to the mental health difficulties they experience. One aspect of psychological wellbeing that has not been well explored in relation to parental support is Quality of Life (QoL).
Acute Myeloid Leukemia: Selecting Induction Therapy Based on Biological Disease Factors
Authors: Rebecca Olin
Journal: Journal of the National Comprehensive Cancer Network (2023)

Greater insight into the role of biologic disease factors in acute myeloid leukemia (AML) has led to more effective and personalized treatment options. Data presented at the NCCN 2023 Annual Congress: Hematologic Malignancies reflected the rapidly evolving treatment landscape, showcasing the significance of combination therapies and precision medicine in managing different AML subtypes. For patients deemed fit for induction with favorable-risk cytogenetics, the standard of care has moved to combining the 7 + 3 regimen with gemtuzumab ozogamicin. Alternatively, for patients with FLT3 -mutated disease, a more intensified approach involving the addition of midostaurin or newer therapies, such as quizartinib, to standard induction treatment has shown improved outcomes. For patients with AML who are unfit for standard induction, treatments combining hypomethylating agents with venetoclax, as well as therapies involving IDH1/2 and FLT3 inhibitors for specific genetic subtypes, offer encouraging alternatives in managing the disease.
TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization
Authors: Jingshu Tang, Yuying Kang, Yujun Zhou, Nianying Shang, Xinnan Li, Hongyue Wang, Jiaqi Lan, Shuai Wang, Lei Wu, Ying Peng
Journal: Journal of Clinical Investigation (2023)

Blood–brain barrier (BBB) disruption is a serious pathological consequence of traumatic brain injury (TBI), for which there are limited therapeutic strategies. Tissue inhibitor of metalloproteinase-2 (TIMP2), a molecule with dual functions of inhibiting matrix metalloproteinase (MMP) activity and displaying cytokine-like activity through receptor binding, has been reported to inhibit VEGF-induced vascular hyperpermeability. Here, we investigate the ability of TIMP2 to ameliorate BBB disruption in TBI and the underlying molecular mechanisms. Both TIMP2 and AlaTIMP2, a TIMP2 mutant without MMP-inhibiting activity, attenuated neurological deficits and BBB leakage in TBI mice, as well as inhibited junctional protein degradation and translocation to reduce paracellular permeability in HBMECs exposed to hypoxic plus inflammatory insult. Mechanistic studies revealed that TIMP2 interacted with integrin α3β1 on endothelial cells (ECs), inhibiting Src activation-dependent VE-Cadherin phosphorylation, VE-Cadherin/catenin complex destabilization and subsequent VE-Cadherin internalization. Notably, localization of VE-Cadherin on the membrane was critical for TIMP2-mediated EC barrier integrity. Furthermore, TIMP2-mediated increased membrane localization of VE-Cadherin enhanced the level of active Rac1, thereby inhibiting stress fiber formation. Together, our studies have identified an MMP-independent mechanism by which TIMP2 regulates EC barrier integrity after TBI. TIMP2 may be a therapeutic agent for TBI and other neurological disorders involving BBB breakdown.
A functional mini-GDE transgene corrects impairment in models of glycogen storage disease type III
Authors: Antoine Gardin, Jérémy Rouillon, Valle Montalvo-Romeral, Lucille Rossiaud, Patrice Vidal, Romain Launay, Mallaury Vie, Youssef Krimi Benchekroun, Jérémie Cosette, Bérangère Bertin, Tiziana La Bella, Guillaume Dubreuil, Justine Nozi, Louisa Jauze, Romain Fragnoud, Nathalie Daniele, Laetitia Van Wittenberghe, Jérémy Esque, Isabelle André, Xavier Nissan, Lucile Hoch, Giuseppe Ronzitti
Journal: Journal of Clinical Investigation (2023)

Glycogen storage disease type III (GSDIII) is a rare inborn error of metabolism affecting liver, skeletal muscle, and heart due to mutations of the AGL gene encoding for the glycogen debranching enzyme (GDE). No curative treatment exists for GSDIII. The 4.6 kb GDE cDNA represents the major technical challenge toward the development of a single recombinant adeno-associated virus (rAAV)-derived vector gene therapy strategy. Using information on GDE structure and molecular modeling, we generated multiple truncated GDEs retaining activity. Among them, an N-terminal-truncated mutant ∆Nter2-GDE had a similar efficacy in vivo compared to the full-size enzyme. A rAAV vector expressing ∆Nter2-GDE allowed significant glycogen reduction in heart and muscle of Agl–/– mice three months after intravenous injection, as well as normalization of histology features and restoration of muscle strength. Similarly, glycogen accumulation and histological features were corrected in a recently generated Agl–/– rat model. Finally, transduction with rAAV vectors encoding ∆Nter2-GDE corrected glycogen accumulation in an in vitro human skeletal muscle cellular model of GSDIII. In conclusion, our results demonstrated the ability of a single rAAV vector expressing a functional mini-GDE transgene to correct the muscle and heart phenotype in multiple models of GSDIII, supporting its clinical translation to GSDIII patients.
Management of Newly Diagnosed Multiple Myeloma Based on Risk Stratification
Authors: Natalie S. Callander
Journal: Journal of the National Comprehensive Cancer Network (2023)

In the context of newly diagnosed multiple myeloma, recent advances in risk assessment have influenced treatment decisions and paved the way for more individualized approaches. The current NCCN Guidelines for Multiple Myeloma outline the updated staging system, highlight various high-risk features for disease progression/relapse, and provide evidence-based recommendations for myeloma therapy. Although the therapeutic landscape continues to shift toward increased risk adaptability, ongoing efforts should place an emphasis on tackling modifiable risks.
CTRP4/interleukin-6 receptor signaling ameliorates autoimmune encephalomyelitis by suppressing Th17 cell differentiation
Authors: Lulu Cao, Jinhai Deng, Wei Chen, Minwei He, Ning Zhao, He Huang, Lu Ling, Qi Li, Xiaoxin Zhu, Lu Wang
Journal: Journal of Clinical Investigation (2023)

C1q/TNF related protein 4 (CTRP4) is generally thought to be released extracellularly and plays a critical role in energy metabolism and protecting against sepsis. However, its physiological functions in autoimmune diseases have not been thoroughly explored. In this study, we demonstrated that Th17 cell-associated experimental autoimmune encephalomyelitis was greatly exacerbated in Ctrp4-/- mice compared to WT mice due to increased Th17 cell infiltration. The absence of Ctrp4 promoted the differentiation of naïve CD4+ T cells into Th17 cells in vitro. Mechanistically, CTRP4 interferes with the interaction between IL-6 and IL-6R by directly competing to bind with IL-6R leading to suppression of IL-6-induced activation of STAT3 pathway. Furthermore, the administration of recombinant CTRP4 protein ameliorated the disease symptoms. In conclusion, our results indicate that CTRP4, as an endogenous regulator of the IL-6 receptor signaling pathway, may be a potential therapeutic intervention for Th17 driven-autoimmune diseases.
Revolutionizing Hematologic Cancer Treatment: The Promise of Bispecific T-Cell Engagers
Authors: Lihua E. Budde, Stacy Pak, Lauren R. Seipel
Journal: Journal of the National Comprehensive Cancer Network (2023)

The advent of bispecific T-cell engager (TCE) therapies has marked a turning point in the management of hematologic malignancies. Several clinical trials of these agents have led to approvals from the FDA, resulting in their subsequent incorporation into standard patient care. Although ongoing efforts are being made to optimize bispecific TCE therapies, a focus on their equitable distribution is needed. At the NCCN 2023 Annual Congress: Hematologic Malignancies, panelists presented clinical trial data, 2 case studies, and updates from NCCN Guidelines to develop an evidence-based approach for the use of these immunotherapies in various clinical contexts.
Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via regulation of key regenerative pathways
Authors: Xue-Wei Wang, Shu-Guang Yang, Ming-Wen Hu, Rui-Ying Wang, Chi Zhang, Anish R. Kosanam, Arinze J. Ochuba, Jing-Jing Jiang, Ximei Luo, Yun Guan, Jiang Qian, Chang-Mei Liu, Feng-Quan Zhou
Journal: Journal of Clinical Investigation (2023)

Current treatments for neurodegenerative diseases and neural injuries face major challenges, primarily due to the diminished regenerative capacity of neurons in the mammalian CNS as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulating mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons following peripheral nerve injury to facilitate spontaneous axon regeneration. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation-dependent and -independent mechanisms. Further investigation revealed that Ezh2 fostered axon regeneration by orchestrating the transcriptional silencing of genes governing synaptic function and those inhibiting axon regeneration, while concurrently activating various factors that support axon regeneration. Notably, we demonstrated that GABA transporter 2, encoded by Slc6a13, acted downstream of Ezh2 to control axon regeneration. Overall, our study underscores the potential of modulating chromatin accessibility as a promising strategy for promoting CNS axon regeneration.
Perioperative Management of Anticoagulation and Antithrombotic Therapy
Authors: Michael B. Streiff
Journal: Journal of the National Comprehensive Cancer Network (2023)

The latest updates to the NCCN Guidelines for perioperative management of anticoagulation and antithrombotic therapies reflect significant changes in the use of bridging anticoagulation. For patients with low- to intermediate-risk atrial fibrillation, the standard of care has shifted toward reduced reliance on bridging anticoagulation. The rationale for this shift is based on the BRIDGE trial, which revealed a 3-fold greater risk of major bleeding without significant reduction in thrombotic outcomes in patients receiving bridging therapy. In patients with mechanical heart valves, findings from the PERIOP2 study led to similar conclusions. Both of these studies have contributed to a paradigm shift in perioperative anticoagulation management, pivoting toward personalized therapy based on patient-specific bleeding and thrombotic risks. For emergent or elective surgeries, the NCCN Guidelines provide a framework for more individualized decision-making, emphasizing the need for ongoing cooperation among physicians, surgeons, and patients.
From immunology to artificial intelligence: revolutionizing latent tuberculosis infection diagnosis with machine learning
Authors: Lin-Sheng Li, Ling Yang, Li Zhuang, Zhao-Yang Ye, Wei-Guo Zhao, Wen-Ping Gong
Journal: Military Medical Research (2023)

Latent tuberculosis infection (LTBI) has become a major source of active tuberculosis (ATB). Although the tuberculin skin test and interferon-gamma release assay can be used to diagnose LTBI, these methods can only differentiate infected individuals from healthy ones but cannot discriminate between LTBI and ATB. Thus, the diagnosis of LTBI faces many challenges, such as the lack of effective biomarkers from Mycobacterium tuberculosis (MTB) for distinguishing LTBI, the low diagnostic efficacy of biomarkers derived from the human host, and the absence of a gold standard to differentiate between LTBI and ATB. Sputum culture, as the gold standard for diagnosing tuberculosis, is time-consuming and cannot distinguish between ATB and LTBI. In this article, we review the pathogenesis of MTB and the immune mechanisms of the host in LTBI, including the innate and adaptive immune responses, multiple immune evasion mechanisms of MTB, and epigenetic regulation. Based on this knowledge, we summarize the current status and challenges in diagnosing LTBI and present the application of machine learning (ML) in LTBI diagnosis, as well as the advantages and limitations of ML in this context. Finally, we discuss the future development directions of ML applied to LTBI diagnosis.
Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice
Authors: Milagros C. Romay, Russell H. Knutsen, Feiyang Ma, Ana Mompeón, Gloria E. Hernandez, Jocelynda Salvador, Snezana Mirkov, Ayush Batra, David P. Sullivan, Daniele Procissi, Samuel Buchanan, Elise Kronquist, Elisa A. Ferrante, William A. Muller, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Craig Horbinski, Elisabeth Tournier‑Lasserve, Adam M. Sonabend, Farzaneh A. Sorond, Michael M. Wang, Manfred Boehm, Beth A. Kozel, M. Luisa Iruela-Arispe
Journal: Journal of Clinical Investigation (2023)

Vascular aging impacts multiple organ systems, including the brain, where it can lead to vascular dementia. However, a concrete understanding of how aging specifically affects the brain vasculature, along with molecular read-outs, remain vastly incomplete. Here we demonstrate that aging is associated with a marked decline in Notch3 signaling in both murine and human brain vessels. To clarify the consequences of Notch3 loss in the brain vasculature, we used single-cell transcriptomics and uncovered that Notch3 inactivation alters regulation of calcium, contractile function, and promotes a notable increase in extracellular matrix. These alterations adversely impact vascular reactivity, manifesting as dilation, tortuosity, microaneurysms, and decreased cerebral blood flow, as observed by MRI. Combined, these vascular impairments hinder glymphatic flow and result in buildup of glycosaminoglycans within the brain parenchyma. Remarkably, this phenomenon mirrors a key pathological feature found in brains of CADASIL patients – a hereditary vascular dementia associated with NOTCH3 missense mutations. Additionally, single-cell RNA sequencing of the neuronal compartment in aging Notch3 null mice has unveiled patterns reminiscent of those observed in neurodegenerative diseases. These findings offer direct evidence that age-related NOTCH3 deficiencies trigger a progressive decline in vascular function, subsequently affecting glymphatic flow and culminating in neurodegeneration.
Immunotherapy of MSI Cancer: Facts and Hopes
Authors: H. Catherine Wilbur, Dung T. Le, Parul Agarwal
Journal: Clinical Cancer Research (2023)

Abstract Microsatellite instability (MSI) is a tumor molecular phenotype that evolves from loss of function in the mismatch repair (MMR) proteins through deleterious germline mutations, epigenetic inactivation, or somatic biallelic mutations. This phenotype is characterized by genomic hyper-mutability, increased neoantigen expression, and a favorable, immune-rich tumor microenvironment. These features confer a greater likelihood of response to treatment with the class of agents known as immune checkpoint inhibitors (ICI) and, potentially, other immune-based therapeutics. MSI as a predictive biomarker for response to treatment with ICIs ultimately led to the first tissue-agnostic approval of pembrolizumab for advanced, previously treated MSI or deficient MMR (dMMR) tumors. Nevertheless, response to ICIs in dMMR/MSI tumors is not universal. Identifying predictors of response and elucidating mechanisms of immune escape will be crucial to continued successful treatment of this subset. In this review, we aim to describe the pathogenesis and key immunologic features of dMMR/MSI tumors, provide a brief overview of the currently approved treatments, and discuss promising novel immune-based therapeutics currently under investigation.
Abstract 13737: Abdominal Aortic Aneurysm Growth is Predicted by Uptake of Ultrasmall Superparamagnetic Particles of Iron Oxide
Authors: Jennifer M Richards, Scott I Semple, Thomas J MacGillivray, Calum Gray, Jeremy P Langrish, Michelle Williams, Marc Dweck, William A Wallace, Graham McKillop, Roderick T Chalmers, O. James Garden, David E Newby
Journal: Circulation (2010)

Background: Abdominal aortic aneurysms are a major cause of death. Prediction of aneurysm expansion and rupture is challenging and currently relies on the simple measure of aneurysm diameter. Using magnetic resonance imaging, we aimed to assess whether areas of cellular inflammation correlated with the rate of abdominal aortic aneurysm expansion. Methods: Stable patients (n=29; 27 male; aged 70±5 years) with asymptomatic abdominal aortic aneurysms (4–6.6 cm) were recruited from a surveillance programme and were imaged in a 3T magnetic resonance imaging scanner before and 24–36 h after administration of ultrasmall superparamagnetic particles of iron oxide (USPIO). The change in T2* value on T2*-weighted imaging was used to detect accumulation of USPIO within the abdominal aortic aneurysm. The aneurysm growth rate was calculated from serial ultrasound measurements. In patients undergoing surgery, a sample of aortic wall was fixed and stained for CD68 (macrophages) and Prussian blue (iron). Results: Histolog...
Exercise and gait/movement analyses in treatment and diagnosis of Parkinson’s Disease
Authors: Johannes Burtscher, Eduardo Martin Moraud, Davide Malatesta, Grégoire P. Millet, Julien F. Bally, Aurélien Patoz
Journal: Ageing Research Reviews (2023)

Cardinal motor symptoms in Parkinson's disease (PD) include bradykinesia, rest tremor and/or rigidity. This symptomatology can additionally encompass abnormal gait, balance and postural patterns at advanced stages of the disease. Besides pharmacological and surgical therapies, physical exercise represents an important strategy for the management of these advanced impairments. Traditionally, diagnosis and classification of such abnormalities have relied on partially subjective evaluations performed by neurologists during short and temporally scattered hospital appointments. Emerging sports medical methods, including wearable sensor-based movement assessment and computational-statistical analysis, are paving the way for more objective and systematic diagnoses in everyday life conditions. These approaches hold promise to facilitate customizing clinical trials to specific PD groups, as well as personalizing neuromodulation therapies and exercise prescriptions for each individual, remotely and regularly, according to disease progression or specific motor symptoms. We aim to summarize exercise benefits for PD with a specific emphasis on gait and balance deficits, and to provide an overview of recent advances in movement analysis approaches, notably from the sports science community, with value for diagnosis and prognosis. Although such techniques are becoming increasingly available, their standardization and optimization for clinical purposes is critically missing, especially in their translation to complex neurodegenerative disorders such as PD. We highlight the importance of integrating state-of-the-art gait and movement analysis approaches, in combination with other motor, electrophysiological or neural biomarkers, to improve the understanding of the diversity of PD phenotypes, their response to therapies and the dynamics of their disease progression.
Assessment and predictive ability of the absolute neutrophil count in peripheral blood for in vivo CAR T cells expansion and CRS
Authors: Man Zhang, Xiaolu Long, Yi Xiao, Jin Jin, Caixia Chen, Jiao Meng, Wanying Liu, Aichun Liu, Liting Chen
Journal: Journal for ImmunoTherapy of Cancer (2023)

Chimeric antigen receptor (CAR) T cell therapy is an advanced and effective immunotherapy for relapsed or refractory B-cell malignancies. High expansion of CAR T cells in vivo and durable antitumor activity indicate a persistent therapeutic response. However, this treatment is linked to a high frequency of adverse events, such as cytokine release syndrome (CRS), which affects its efficacy and can even be life-threatening. At present, a variety of markers associated with clinical response and treatment toxicity after CAR T cells infusion have been reported. Although these biomarkers can act as effective indicators reflecting CAR T cells expansion as well as CRS, they fail to predict the expansion rate of CAR T cells. Hence, further investigation is urgent to find a new biomarker to fill this void. We analyzed the association between the absolute neutrophil count (ANC) and CAR expansion and CRS in 45 patients with B-cell malignancies from two clinical trials. We proposed that ANC could be a practical biomarker for CAR T cells expansion and CRS, and conducted a feasibility analysis on its predictive ability. In this study, 17 B-cell hematological malignancy patients with anti-B-cell maturation antigen CAR-treated and 28 with CAR19/22 T-cell-treated were enrolled and divided into an ANC-absence group and an ANC-presence group. The results showed that ANC absence correlated positively with CAR expansion and the expansion rate. The ANC can be used as a predictive marker for CAR T cells expansion. Moreover, the patients with ANC absence experienced a more severe CRS, and ANC performed a predictive ability for CRS. In addition, the peak serum concentration of several cytokines involved in CRS was higher in patients with ANC absence. Thus, we suggest ANC as an evaluative and predictive biomarker for CAR expansion and CRS during CAR T cell therapy, which can help to maximize clinical efficacy, reduce treatment-related toxicity and prolong survival.
An infection-microenvironment-targeted and responsive peptide-drug nanosystem for sepsis emergency by suppressing infection and inflammation
Authors: Wei He, Daan Fu, Yongkang Gai, Xingxin Liu, Chang Yang, Zhilan Ye, Xu Chen, Jia Liu, Bingcheng Chang
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Sepsis is a life-threatening emergency that causes millions of deaths every year due to severe infection and inflammation. Nevertheless, current therapeutic regimens are inadequate to promptly address the vast diversity of potential pathogens. Omiganan, an antimicrobial peptide, has shown promise for neutralizing endotoxins and eliminating diverse pathogens. However, its clinical application is hindered by safety and stability concerns. Herein, we present a nanoscale drug delivery system (Omi-hyd-Dex@HA NPs) that selectively targets infectious microenvironments (IMEs) and responds to specific stimuli for efficient intervention in sepsis. The system consists of omiganan-dexamethasone conjugates linked by hydrazone bonds which self-assemble into nanoparticles coated with a hyaluronic acid (HA). The HA coating not only facilitates IMEs-targeting through interaction with intercellular-adhesion-molecule-1 on inflamed endotheliocytes, but also improves the biosafety of the nanosystem and enhances drug accumulation in primary infection sites triggered by hyaluronidase . The nanoparticles release dual drugs in IMEs through pH-sensitive cleavage of hydrazone bonds to eradicate pathogens and suppress inflammation. In multiple tissue infection and sepsis animal models, Omi-hyd-Dex@HA NPs exhibited rapid source control and comprehensive inflammation reduction, thereby preventing subsequent fatal complications and significantly improving survival outcomes. The bio-responsive and self-delivering nanosystem offers a promising strategy for systemic sepsis treatment in emergencies.